PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease

Moreno‐Fernandez, Maria E.; Giles, Daniel; Oates, Jarren R; Chan, Christine M.; Damen, Michelle S M A; Doll, Jessica; Stankiewicz, Traci E.; Rothenberg, Marc E.; Chetal, Kashish; Karns, Rebekah; Weirauch, Matthew T.; Romick-Rosendale, Lindsey E.; Xanthakos, Stavra A.; Sheridan, Rachel; Szabo, Sara; Shah, Amy S.; Helmrath, Michael A.; Inge, Thomas H.; Deshmukh, Hitesh; Salomonis, Nathan; Divanovic, Senad

doi:10.1016/j.cmet.2021.04.018

Cited by 87 publications

(88 citation statements)

References 121 publications

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“…In contrast to conventional Th17 cells, ihTh17 cells display increased chromatin accessibility as well as a transcriptomic profile indicative of enhanced glycolytic capacity, CXCR3 activation, and production of inflammatory IFNg, TNFa, and IL-17A (75). As a result, glycolysis inhibition, ihTh17 cell-specific ablation of IFNg, or modulation of CXCR3-CXCL9/10 axis conferred protection against hepatocellular damage and hepatic accumulation of ihTh17 cells in murine models of NASH (75). These findings highlight how the liver microenvironment and metabolism can dictate the function of Th17 cells during NAFLD pathogenesis.…”

Section: Role Of Cd4 T Cells In Nashmentioning

confidence: 90%

“…However, the liver microenvironment and cellular metabolism may govern the acquisition of distinct phenotypes by CD4 T cell subsets. For example, the inflammatory and highly glycolytic CXCR3+ Th17 (ihTh17) cells have been recently implicated in obesity and NAFLD pathogenesis (75). In contrast to conventional Th17 cells, ihTh17 cells display increased chromatin accessibility as well as a transcriptomic profile indicative of enhanced glycolytic capacity, CXCR3 activation, and production of inflammatory IFNg, TNFa, and IL-17A (75).…”

Section: Role Of Cd4 T Cells In Nashmentioning

confidence: 99%

“…For example, the inflammatory and highly glycolytic CXCR3+ Th17 (ihTh17) cells have been recently implicated in obesity and NAFLD pathogenesis (75). In contrast to conventional Th17 cells, ihTh17 cells display increased chromatin accessibility as well as a transcriptomic profile indicative of enhanced glycolytic capacity, CXCR3 activation, and production of inflammatory IFNg, TNFa, and IL-17A (75). As a result, glycolysis inhibition, ihTh17 cell-specific ablation of IFNg, or modulation of CXCR3-CXCL9/10 axis conferred protection against hepatocellular damage and hepatic accumulation of ihTh17 cells in murine models of NASH (75).…”

Section: Role Of Cd4 T Cells In Nashmentioning

confidence: 99%

“…So far, activation of CD8 T cells during NAFL and NASH has been attributed to type I interferons (52), IL-15, and metabolic signals such as acetate and extracellular ATP (45). In Th17 cells, modulation of cell-intrinsic glycolysis has been shown to decrease their inflammatory function during NAFLD (75), highlighting the need to determine how cellular metabolism in T cell development, activation, differentiation, and function during NASH. Additional studies are also needed to clarify if T cell activation in the liver during NASH is antigen-dependent and the identity of the antigenic stimuli.…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

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Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

et al. 2021

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Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. A significant proportion of patients with NAFLD develop a progressive inflammatory condition termed nonalcoholic steatohepatitis (NASH), which may eventually advance to cirrhosis and hepatocellular carcinoma (HCC). NASH is characterized by steatosis, hepatocyte ballooning, and lobular inflammation. Heightened immune cell infiltration is a hallmark of NASH, yet the mechanisms whereby hepatic inflammation occurs in NASH and how it contributes to disease initiation and progression remain incompletely understood. Emerging evidence indicates that intrahepatic T cell immune mechanisms play an integral role in the pathogenesis of NASH and its transition to HCC. In this review, we summarize the current knowledge regarding the T cell-mediated mechanisms of inflammation in NASH. We highlight recent preclinical and human studies implicating various subsets of conventional and innate-like T cells in the onset and progression of NASH and HCC. Finally, we discuss the potential therapeutic strategies targeting T cell-mediated responses for the treatment of NASH.

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Section: Role Of Cd4 T Cells In Nashmentioning

confidence: 90%

Section: Role Of Cd4 T Cells In Nashmentioning

confidence: 99%

Section: Role Of Cd4 T Cells In Nashmentioning

confidence: 99%

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

See 2 more Smart Citations

Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

et al. 2021

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“…Recent studies have shown that proinflammatory mediators may regulate metabolic sequelae [ 61 ]. Further, specific hepatic inflammatory Th17 cells specifically contribute to obesity induced liver damage [ 62 ]. Combined future investigations in these areas will be critical to pinpoint the interplay of immune cells and tissue non-hematopoietic cells utilizing IL-4Rα-dependent signaling in the setting of HF versus HF + HC diet exposure and the relevance of such biological processes to obesity-driven metabolic disease progression.…”

Section: Discussionmentioning

confidence: 99%

Non-hematopoietic IL-4Rα expression contributes to fructose-driven obesity and metabolic sequelae

et al. 2021

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Objective The risks of excess sugar intake in addition to high-fat diet consumption on immunopathogenesis of obesity-associated metabolic diseases are poorly defined. Interleukin-4 (IL-4) and IL-13 signaling via IL-4Rα regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in obesity. However, the contribution of IL-4Rα to sugar rich diet-driven obesity and metabolic sequelae remains unknown. Methods WT, IL-4Rα-deficient (IL-4Rα−/−) and STAT6-deficient mice (STAT6−/−) male mice were fed low-fat chow, high fat (HF) or HF plus high carbohydrate (HC/fructose) diet (HF + HC). Analysis included quantification of: (i) body weight, adiposity, energy expenditure, fructose metabolism, fatty acid oxidation/synthesis, glucose dysmetabolism and hepatocellular damage; (ii) the contribution of the hematopoietic or non-hematopoietic IL-4Rα expression; and (iii) the relevance of IL-4Rα downstream canonical STAT6 signaling pathway in this setting. Results We show that IL-4Rα regulated HF + HC diet-driven weight gain, whole body adiposity, adipose tissue inflammatory gene expression, energy expenditure, locomotor activity, glucose metabolism, hepatic steatosis, hepatic inflammatory gene expression and hepatocellular damage. These effects were potentially, and in part, dependent on non-hematopoietic IL-4Rα expression but were independent of direct STAT6 activation. Mechanistically, hepatic ketohexokinase-A and C expression was dependent on IL-4Rα, as it was reduced in IL-4Rα-deficient mice. KHK activity was also affected by HF + HC dietary challenge. Further, reduced expression/activity of KHK in IL-4Rα mice had a significant effect on fatty acid oxidation and fatty acid synthesis pathways. Conclusion Our findings highlight potential contribution of non-hematopoietic IL-4Rα activation of a non-canonical signaling pathway that regulates the HF + HC diet-driven induction of obesity and severity of obesity-associated sequelae.

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Overexpressed PKM2 promotes macrophage phagocytosis and atherosclerosis

Gai

Liu

et al. 2022

Anim Models and Exp Med

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Background The expression of pyruvate kinase muscle 2 (PKM2) is augmented in macrophages of patients with atherosclerotic coronary artery disease. The role of PKM2 in atherosclerosis is to be determined. Methods Global and myeloid cell‐specific PKM2 knock‐in mice with ApoE −/− background ( ApoE −/− , PKM2 KI/KI and Lyz2‐cre , ApoE −/− , and PKM2 flox/flox ) were produced to evaluate the clinical significance of PKM2 in atherosclerosis development. Wild‐type and PKM2 knock‐in macrophages were isolated to assess the function of PKM2 in macrophage phagocytosis. Atherosclerotic mice were treated with PKM2 inhibitor shikonin (SKN) to evaluate the therapeutic potential of PKM2 suppression in atherosclerosis. Results Oxidized low‐density lipoprotein (oxLDL) upregulated PKM2 in macrophages. PKM2 in return promoted the uptake of oxLDL by macrophages. Overexpressed PKM2 accelerated atherosclerosis in mice. SKN blocked the progress of mouse atherosclerosis. Conclusions PKM2 accelerates macrophage phagocytosis and atherosclerosis. Targeting PKM2 is a potential therapy for atherosclerosis.

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PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease

Cited by 87 publications

References 121 publications

Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

Non-hematopoietic IL-4Rα expression contributes to fructose-driven obesity and metabolic sequelae

Overexpressed PKM2 promotes macrophage phagocytosis and atherosclerosis

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